Two novel cDNAs, IA-1 and IA-2, isolated from a human insulinoma subtraction library (ISL-153) were subjected to intensive studies. IA-1 gene was isolated and characterized to be an intronless gene which localized at chromosome 20p11.2 by fluorescence in situ hybridization. We have conducted a study of IA-1 gene expression in a panel of 64 endocrine and non-endocrine human lung cancer cell lines and compared it with two other neuroendocrine markers, chromogranin A and L-dopa decarboxylase. The result indicated that IA-1 is a candidate marker of neuroendocrine differentiation of human lung tumors. IA-1 mRNA was detected by Northern blot analysis in 97% (30/31) of small cell lung cancer (SCLC) cell lines. In contrast, IA-1 mRNA was detected in only 13% (4/30) of non-small cell lung cancer (NSCLC) cell lines. In most of the lung cancer cell lines examined, IA-1 showed high concordance with the other neuroendocrine markers, L-dopa decarboxylase and chromogranin A. The second cDNA, IA-2, was characterized to be a new member of receptor-type protein tyrosine phosphatase which expressed in normal enriched islets and brain tissues. We have also cloned and sequenced the mouse counterpart of IA-2 from a normal mouse brain library. Mouse brain IA-2 revealed 85% and 92% homology to the human insulinoma IA-2 molecule in nucleotide sequence and amino acid sequence respectively. Furthermore, both molecules share 99.7% identify in a stretch of 300 amino acids of intracellular PTP domain.